1. The Field of the Invention
The present invention relates to methods of detecting risk for cardiac disease. More specifically, the present invention relates to genetic based methods for detecting a risk for a cardiac dysrhythmia in a patient and for diagnosing Andersen's Syndrome.
2. The Relevant Technology
Andersen's Syndrome (AS) is a rare disorder characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. Canun, S., et al. (1999) Am J Med Genet 85: 147-56; Sansone, V. et al. (1997) Ann Neurol 42: 305-12; Tawil, R. et al. (1994) Ann Neurol 35: 326-30. The dysmorphology includes short stature, scoliosis, clinodactyly, wide-set eyes, small or prominent ears that are low set or slanted, a small chin, cleft pallet, and broad forehead. AS occurs either sporadically or as an autosomal dominant trait. In AS families, expression of the characteristic traits is highly variable. Thus, it is likely that the AS protein plays a complex role in development and cell excitability with some redundancy with other proteins.
The periodic paralyses and nondystrophic myotonias are a group of muscle disorders manifest by abnormal muscle relaxation (myotonia). This myotonia results from muscle hyperexcitability that sometimes transitions to inexcitability resulting in episodic weakness. Ventacular tachydysrhythmias are analogous to myotonia of skeletal muscle in that hyperexcitability leads to an abnormal, albeit highly organized, series of heart contractions that can also transition to inexcitability thus leading to death from cardiac dysrhythmias. The electrophysiological features of such diseases suggest an underlying defect in membrane excitability. Approximately 300,000 Americans die of cardiac dysrhythmias each year. Kannel, W. B. et al. (1987) Am Heart J 113, 799-804; Willich, S. N. et al. (1987) Am J Cardiol 60: 801-6.
Many of the persons who die of cardiac dysrhythmias do not exhibit heart problems prior to death. The fatal cardiac dysrhythmia may be triggered by aerobic exercise such as running. Thus, a patient may be at risk for cardiac dysrhythmias without exhibiting risk factors and without knowing to avoid certain types of activities or exercise. Moreover, certain medications are known to induce cardiac dysrhythmias in patients with heart conditions. However, when a patient does not exhibit any of the factors which would indicate a risk for cardiac dysrhythmias prior to a deadly episode, medical professionals cannot know what drugs to avoid prescribing to a patient.
Sudden Infant Death Syndrome (SIDS) is the leading cause of death in infants between 1 month and 1 year of age. Most SIDS deaths occur when a baby is between 1 and 4 months of age. SIDS is the medical term used to describe the sudden death of an infant under one year of age that remains unexplained after a complete investigation, which includes an autopsy, examination of the death scene, and review of the symptoms or illnesses the infant had prior to dying and any other pertinent medical history. A precise cause of SIDS is not known. However, sleep-induced arrhythmias may be a factor in SIDS. It has been hypothesized that changes in the activity of the autonomic nervous system during sleep could precipitate an arrhythmia resulting in sudden death.
The electrical properties of excitable tissues such as skeletal muscle, heart and neurons are determined, in part, by a number of ion channels that work in concert to provide properties appropriate for the function of each tissue. The first ion channel mutations which were shown to contribute to an episodic disorder were characterized about decade ago when mutations in SCN4A, which encodes a voltage-gated sodium channel, were shown to cause hyperkalemic periodic paralysis. Ptacek, L. J. et al. (1991) Cell 67: 1021-7; Rojas, C. V. et al. (1991) Nature 354: 387-9. This rare muscle disease formed the basis of the growing group now known as the channelopathies and led to predictions that cardiac dysrhythmias and epilepsies would be caused by mutations in homologous genes. Ptacek, L. J. et al. (1991) Cell 67: 1021-7. Similarities between these different episodic disorders suggested similar molecular bases of these disorders. The occurrence of both periodic paralysis and long QT (LQT) in Andersen's Syndrome strongly supports this hypothesis. Tawil, R. et al. (1994) Ann Neurol 35: 326-30. Since this initial discovery, periodic paralysis has been associated with mutations in voltage-gated K+, Na+, Ca2+, and Cl− channels, while LQT has been associated with mutations in voltage-gated K+ and Na+ channels. Jen, J. & Ptacek, L. J., METABOLIC AND MOLECULAR BASES OF INHERITED DISEASE, pp. 5223-5238(C. R. Scriver et al., McGraw-Hill, 2001); Sanguinetti, M. (2001) Cell 104:569-580. To date, no human disorders involving cardiac and skeletal muscle have been attributed to mutations in inward rectifying K+ channels.
Inward rectifier K+ channels (Kir) play a role in controlling cell excitability and resting membrane potential in many different tissues including heart, brain, and skeletal muscle. Doupnik, C. A. et al. (1995) Curr Opin Neurobiol 5: 268-77; Jan, L. Y., & Jan, Y. N. (1997) J Physiol 505:267-82; Nichols, C. G., & Lopatin, A. N. (1997) Annu Rev Physiol 59,171-91. Generally, Kir channels contribute to the final repolarization phase of cardiac action potentials by passing small amounts of K+ out of the cell and bringing the membrane potential back to resting membrane potential (Em). Structurally, Kir channels resemble voltage-gated K+ channels; however, they are missing the four N-terminal transmembrane domains including the S4 voltage sensor. Kir channels consist of an intracellular N-terminal domain, two transmembrane segments M1 and M2) flanking a pore region, and an intracellular C-terminal segment; M1 and M2 correspond to S5 and S6 of voltage-gated channels. Kir subunits are believed to form either homo- or heterotetramers. Yang, J. et al. (1995) Neuron 15: 1441-7.
Kir2.1 (IRK1), encoded by the gene KCNJ2, is a member of the Kir2.x family of inward rectifying K+ channels expressed predominantly in heart, brain, and skeletal muscle. Kubo, Y. et al. (1993) Nature 362,127-33 Raab-Graham, K. F. et al. (1994) Neuroreport 5, 2501-5. The function of Kir2.1 has been studied primarily in the heart. It is classified as a strong inward rectifier, that is, almost no current passes through these channels at potentials positive to −40 mV. Thus, strong inward rectification prevents excess loss of K+ during the plateau phase of the cardiac action potential, but allows outward K+ flux during terminal repolarization and diastolic phases of the action potential. Sanguinetti, M. C., & Tristani-Firouzi, M., CARDIAC ELECTROPHYSIOLOGY: FROM CELL TO BEDSIDE, pp. 79-86., (D. P. Zipes, & J. Jalife, eds., W. B. Saunders, 2000).
Much less is known about the role of Kir2.1 in other tissues such as the brain and skeletal muscle. It is likely that the role of Kir2.1 in skeletal muscle and neurons is similar to its role in the heart by controlling the resting membrane potential and the terminal repolarization phase of the action potential. Interestingly, there is some evidence suggesting that Kir2.1 has some functional significance outside of modulating the action potential of neurons and myocytes. Kir2.1 knockout mice have a complete cleft of the secondary palate and a slight narrowing of the maxilla. Zaritsky, J. J. et al. (2000) Circ Res 87: 160-6. In rat, Kir2.1 MRNA is present by embryonic day 12 in bone associated structure of the head, limb, and body. Karschin, C., & Karschin, A. (1997) Mol Cell Neurosci 10, 131-48. These findings provide some evidence for an underlying developmental function of Kir2.1.
Currently the genetic cause of Andersen's Syndrome is not known. Moreover, persons with Andersen's Syndrome have a high risk for cardiac dysrhythmias. Accordingly it would be an advancement in the art to provide a gene responsible for the Andersen's Syndrome phenotype. It would be a further advancement to provide a diagnostic test for Andersen's Syndrome. It would be a further advancement to provide a method for detecting a risk for cardiac dysrhythmias in a patient.